Role of NK cells in control of HCV infection associated hepatocellular carcinoma

Remarkable advances with hepatitis C Virus (HCV) infection therapy have been made over the past 5 years,.
At the same time, the peak of morbidity for the HCV epidemic, including outcomes such as cirrhosis and
hepatocellular carcinoma (HCC) will not occur until 2030. In fact, HCC is one of the fastest growing cancer
related causes of death in the US. Certainly, at some point successful therapy for HCV will reduce the
incidence of HCC. Though when this will be realized is unclear, in part due to the fact that the chronic HCV-
infected patient population is aging, and older age HCV-infected patients do not appear to derive the same
reduction in morbidity after successful HCV therapy as do their younger counterparts. At present, our local VA
station (Station 541, Cleveland) follows 3,428 HCV patients, and over the past 3 years has treated over 1,500
of these with IFN-free therapy. Still, we accrue 25-43 new HCC cases/year, running at a steady rate over the
past 6 years. Better strategies to more precisely identify those at high risk for HCC, and treat early HCC are
much needed to curb this morbidity/mortality. PD1 blockade is an emerging therapy, and while a role for T cells
in mediating effects of PD1 blockade have been defined, a role for NK cell activity is less defined. At the same
time NK cells are a dominant lymphocyte population within the liver, NK cells are known to contribute to control
of HCV infection itself, and NK cells have anti-cancer effector function. We will follow our well characterized
HCV infected patient population, taking an NK cell, pathway focused approach to evaluate the anti-tumor host
immune response that precedes HCV associated HCC diagnosis, to help identify both predictive markers and
new treatment strategies. We hypothesize that NK cells play an integral role in host defense against HCV
associated HCC, that selective enhancement of NK cell immune function through modulation of the IFN
response or PD1 signaling can be harnessed to improve host anti-HCC immunity with therapeutic potential.
Defining NK cell immunity that precedes HCC diagnosis will inform when and how to best inform PD1 or NK
targeted clinical trial design, and potentially provide biomarkers of disease risk or onset. We will investigate this
hypothesis with the following aims: Aim 1: Determine the role of PD1 on NK cell expansion and anti-HCC
activity. Aim 2: Determine the effect of selective targeting the Long Non-Coding RNA (lncRNA) NRIR
(negative regulator of interferon response) in enhancing IFN-dependent anti-HCC activity. Aim 3:
Define NK cell activation state, function, PD1 pathway engagement and IFN regulatory pathway
engagement prior to diagnosis of HCC.

Grant Number: 5I01BX001894-12
NIH Institute/Center: VA
Principal Investigator: Donald Anthony